Herpes simplex virus (HSV), types 1 and 2, causes recurrent infections that range in severity from benign to serious. HSV emerges from latency in neurons to infect the skin and other tissues in the presence of a competent cellular immune system. The D glycoprotein (gD) of HSV, a transmembrane protein located in the virion envelope, initiates infection by binding to cellular receptors [Spear et al. (1993) In, Viral Fusion Mechanisms. Ed. Bentz. CRC press, Boca Raton]. Recently, a cellular protein used by HSV for infection was identified and given the term HSV entry mediator (HVEM) [Montgomery et al. (1996) Cell 87:427]. HVEM is a transmembrane type 1 protein with a cysteine-rich extracellular domain that exhibits significant homology with receptors for tumor necrosis factor (TNF)-related cytokines [Smith et al. (1994) Cell 76:959; Ware et al. (1995) in, Pathways of Cytolysis. Eds. Griffiths and Tschopp. Springer-Verlag, Basel]. Many of the TNF superfamily members initiate a variety of cellular responses necessary to mount effective inflammatory and immune responses.
TNF is a type 2 transmembrane protein [Pennica et al. (1984) Nature 312:724] that is proteolyzed to form the secreted protein [Black et. al. (1997) Nature 385:729], whereas LT.alpha. lacks a transmembrane domain [Gray et. al. (1984) Nature 312:721] and is exclusively secreted as a homotrimer (in this form it was also known as TNF.beta.). When expressed as a surface protein, LT.alpha. is associated with a 33 kDa protein [Androlewicz et al. (1992) J. Biol. Chem. 267:2542], termed LT.beta. [Browning et al. (1993) Cell 72:847], also a type 2 transmembrane glycoprotein, in heterotrimers of .alpha.1.beta.2 and .alpha.2.beta.1 subunit ratios [Androlewicz et al., cited supra; Browning et. al. (1996) J. Biol. Chem. 271:8618]. LT.alpha. and TNF both bind and signal through two receptors, the 55-60 kDa TNF receptor (TNFR60; CD120a or type 1) [Schall et al. (1990) Cell 61:361; Loetscher et al. (1990) Cell 61:351] and the 75-80 kDa TNFR (TNFR80; type 2 or CD120b) [Smith et al. (1990) Science 248:1019]. By contrast, the surface LT.alpha.1.beta.2 complex is recognized specifically by the LT.beta. receptor (LT.beta.R) [Crowe et al. (1994) Science 264:707], which does not bind either LT.alpha. or TNF [Crowe et al. (1994) Science 264:707] whereas both TNFRs bind the LT.alpha.2.beta.1 heterotrimer [Crowe et al. (1994) Science 264:707; Browning et al. (1995) J. Immunol. 154:33].
Genetic deletions of LT.alpha. and LT.beta. genes in mice have revealed roles for these two genes in the development of lymph nodes and Peyer's patches [De Togni et al. (1994) Science 264:703; Banks et al. (1995) J. Immunol. 155:1685], and along with TNF and TNFR60, are also critical cytokines controlling the formation of germinal centers and immunoglobulin isotype switching (e.g., IgA production) during immune responses in adults [Matsumoto et al. (1996) Science 271:1289; Mariathasan et al. (1995) J. Inflammation 45:72]. Most studies have pointed towards the LT.alpha.1.beta.2/LT.beta.R as the critical cytokine-receptor system controlling these functions [Crowe et al. (1994) Science 264:707; Koni et al. (1997) Immunity 5:491; Ettinger et al. (1996) Proc. Natl. Acad. Sci. USA 93:13102; Rennert et al. (1996) J. Exp. Med. 184:1999].